Hepatic adipose infiltration is also termed as hepatic adipose degeneration, which refers to the lesions due to excessive lipopexia in hepatic cells induced by various kinds of reasons. It can be termed as hepatic adipose infiltration when fatty content is higher than 5% of the weight of liver (wet weight) (it can be as high as 40-50% at the most) or higher than 30% of the liver parenchyma in histology. Hepatic adipose infiltration may be induced by various kinds of diseases and reasons, the most common causes include obesity, alcoholism and diabetes, and further include nutritional disturbance, drug poisoning, pregnancy and the like. With continuous improvements in living standard of people, changes in diets and life style, the incidence rate of hepatic adipose infiltration has increased yearly and reached 10% of the average population, and it can be as high as 50-60% in specific populations with obesity, alcohol addict or diabetes. It is previously proposed that hepatic adipose infiltration is a benign lesion and it progresses slowly. However, it has been found in recent years that hepatic fibrosis is found about 25% of the patients and 1.5-8% of the patients may develop into hepatic cirrhosis. While 20% of the patients suffering from non-alcoholic fatty liver may develop into hepatic cirrhosis, 30-40% of them die of liver related diseases, and some of them may suffer from sub-acute hepatic failure and liver cancer. Therefore, prevention and treatments on hepatic adipose infiltration are very important for preventing progression of chronic liver disease and improving prognosis.
Currently, effective drugs are still unavailable for hepatic adipose infiltration, and the clinical practices still focus on removal of etiological factors, active treatments on primary diseases and maintenance of reasonable dietary regimen, while drugs only play adjunctive roles. The common drugs mainly focus on blood fat reduction, protection over hepatic cells and the like aspects, and effective therapeutic methods directly taking effects on hepatic lipidoses are still vacant.
On the other hand, with the improvements in living standard and the changes in diet constitution of people as well as the acceleration of aging of the society, the incidence rate of hyperlipemia has continuously increased and the hyperlipemia becomes a common and multiple disease. It has been investigated in previous studies that about 90 million people in our country suffer from hyperlipemia. Hyperlipemia has become a common disease in middle-aged and senile people, while various cardiovascular and cerebrovascular diseases induced by hyperlipemia have become a major cause threatening the lives of middle aged and senile people.
Blood fats mainly refer to cholesterol and triglyceride in serum. Hyperlipemia is a disease in which plasma levels of cholesterol and (or) triglyceride increase due to various kinds of reasons, and it is the pathological basis for inducing and aggravating artherosclerosis and an independent risk factor leading to artherosclerosis, angina, myocardial infarction, cerbral infarction, renal impairments and the like diseases of arterial embolism. Generally, hyperlipemia can be simply classified into hypercholesteremia, hypertriglyceridemia and mixed hyperlipemia. The diets of Chinese people are characterized by high sugar and low fat, and it has been investigated that sugar accounts for 76-79% of the gross calorific value, but fats only account for 8.4-10.6%, while the incidence rate of hyperlipemia is as high as 11%, and endogenous hypertriglyceridemia is the most common one. Drinking alcohol also has significant effects on plasma triglyceride level. In the sensitive individuals, even drinking alcohol at moderate amount may lead to hypertriglyceridemia. Alcohol can increase the synthesis rate of lipids in vivo, reduce the proportion of oxidized fatty acids and increase the proportion of esterified fatty acids. Moreover, alcohol can also reduce the activity of lipoproteinesterase and slow down the catabolism of triglyceride.
Blood fat is an important substance in human body, and plays many important roles, however, it can not exceed a certain level. Once blood fat is excessive, “dense blood” may be caused, and it will deposit on vessel wall and forms atherosclerotic plaques, and vessel wall is thickened, and the endangium becomes rough, and the lumen becomes narrow, thus it may lead to forming of thrombus or even blocking up of the lumen. If it takes place in coronary artery, it may lead to insufficient myocardial blood-supply, and heart-stroke or even myocardial infarction may happened; if it takes place in kidney, it may lead to renal arterial sclerosis and renal failure. Furthermore, hyperlipemia may lead to hypertension, and cause gallstone and pancreatitis, and aggravate hepatitis and the like diseases. Recent studies have shown that hypertriglyceridemia is an independent risk factor for coronary heart disease. Hypertriglyceridemia is directly related to death due to coronary heart disease or cardiovascular events (angina and myocardial infarction), or directly related when low HDL-cholesterol level is concurrent, or this correlation is reinforced when low HDL-cholesterol level is concurrent. Hypertriglyceridemia is the manifestation for abnormal lipoprotein metabolism, which is always concurrent with decrease in HDL level and increase in of small and dense LDL level. Small and dense LDL has strong effects in inducing artherosclerosis. Furthermore, hypertriglyceridemia is always concurrent with hyperinsulinemia, insulin resistance and hypercoagulabale state. Extremely high concentration of TG may further lead to acute pancreatitis.
Increase in blood fat is a slow process. Regulations on blood fat particularly elimination of the adverse effects of blood fat also require a continuous process, therefore, patients should select blood fat reducing drugs with significant therapeutic efficacy and mild toxic and side effects according to their different pathogenetic conditions. Control over hyperlipemia normally requires a long period or even all the life, and the expense is relatively high, and all of the currently available blood-fat reducing drugs have certain side effects. The common blood-fat reducing drugs now include statins, fibrates, chelating agents of cholic acid, nicotinic acid and other blood-fat reducing drugs. Treatments on hypertriglyceridemia are mainly based on drugs, and traditional Chinese drugs for blood-fat reducing have played important roles in reducing triglyceride, for example, the fourth generation of Jiangzhining granules of Junshan has been widely used in clinical practice since its therapeutic efficacy is accurate and the side effects are mild.
In recent years, people have made great efforts in studying and developing RNAi drugs, and RNAi drugs have shown extremely tremendous prospective in genetic diseases, tumors and other helpless diseases for human. RNAi (RNA interference) is a sequence-specific post-transcriptional gene silencing induced by double-strand RNA whose sequence is homologous to the target gene. siRNAs (small interfering RNAs) or small RNAs are RNA fragments with length of 19-23 nucleotides, and these fragments have been confirmed to be essential for RNA interference. siRNA forms RNA-induced silencing complex (RISC) with corresponding endogenous enzymes and proteins, and the sense strand of the double-strand siRNA is excluded from the complex during RNA interference, while the antisense strand directs the RISC to bind to corresponding site in the target mRNA, subsequently the target mRNA is degraded by ribonuclease III in the complex and thus the expression of the target gene is shut off. The phenomenon of RNA interference can not only provide a economical, rapid and efficient technical approach to inhibit gene expression, but also open new ideas for gene function determination, signaling pathway of cells, gene therapy and the like aspects. In comparison to traditional small molecule drugs and antibodies, RNAi therapy has the advantages as followed: (1) the process from the target to the drug is significantly shortened by reasonably designing drugs according to the sequence of the target gene; (2) the synthetic routes of RNAi drugs are almost identical; (3) RNAi therapy can be used target any gene, including non-drug and non-protein genes; (4) RNAi drugs are highly specific. Due to the advantages as mentioned above, many pharmaceutical companies have begun to develop RNAi drugs. siRNA drugs for hepatic adipose infiltration and hyperlipemia are still not available now all over the world, therefore, the application of siRNA in developing drugs for hepatic adipose infiltration and hyperlipemia will bring about significant influences on prevention and treatments on patients with hepatic adipose infiltration and hyperlipemia.